Abstract Surgical site infections occurring post-operatively are the single largest cause of healthcare- associated infections, affecting 157,500 patients in the US and costing billions of dollars annually. With the rapid emergence of multi-resistance among bacteria infecting the skin, including the growing population of diabetic patients, and with no new antibiotics coming down the pipeline, there is a dire clinical need for alternate strategies to combat skin infections. In view of the recent successes of immunotherapy in curing several lethal cancers, coopting the host's own immune system to combat skin infections is a viable possibility. We reasoned that a potential target of immunotherapy in the skin are mast cells (MCs). Indeed, we have found that MCs in the skin can contribute to bacterial clearance through the recruitment of MCs. Recently we discovered that a subset of dendritic cells found in close proximity to MCs in the dermis play a key role in wound healing by inducing rapid reepithelization of injured skin. Since wound healing follows bacterial clearance from infected skin, we hypothesis that these dendritic cells may contribute to wound healing following MC activation. We have previously demonstrated that mast cell activators (MCAs) are powerful and safe adjuvants when combined with various vaccines. Here, we have hypothesized that applying the same MCAs to infected skin would accelerate bacterial clearance and wound healing even without the use of antibiotics. To validate these ideas and extend our studies we propose the following: (i) investigate the multifaceted role of MCs and dendritic cells in promoting bacterial clearance and wound healing and (ii) Investigate the use of MCAs in promoting clearance of bacteria and wound healing following infection by several prominent skin pathogens and establishing the underlying basis for this protection.